Assessing Anticoagulation in Neonates With Congenital Diaphragmatic Hernia During Extracorporeal Membrane Oxygenation: Does Anti-Factor Xa or Thromboelastometry Provide Additional Benefit?

Objective: The optimal management of anticoagulation in neonatal/pediatric patients during extracorporeal membrane oxygenation (ECMO) has not been established yet and varies greatly among ECMO centers worldwide. Therefore, we aimed to assess whether the use of anti-factor Xa assay and/or thromboelastometry correlate better than activated clotting time with heparin dose in newborns with congenital diaphragmatic hernia during ECMO. We also examined whether these coagulation assays correlate with thrombotic and/or hemorrhagic complications, when the management of anticoagulation is based only on activated clotting time values.Methods: A prospective observational study in a neonatal ECMO center was conducted. We included all neonates with congenital diaphragmatic hernia born in our institution between March 2018 and January 2019 and requiring support with venoarterial ECMO. A total of 26 ECMO runs were analyzed. During the study, the heparin dose was still adjusted according to activated clotting time values. Measurements of anti-factor Xa assay, activated partial thromboplastin time, and a thromboelastometry from the same blood specimen were performed twice a day.Results: Anti-factor Xa levels showed a moderate correlation with heparin dose, whereas the other tests showed a weak correlation. Four patients (17.4%) had thrombotic complications, 2 patients (8.7%) experienced life-threatening bleeding, and in 11 patients (47.8%) disseminated intravascular coagulation (DIC) occurred. Anti-factor Xa levels were lower in the group with thrombotic complications (0.23 vs. 0.27 IU/ml; p = 0.002), while activated partial thromboplastin time was higher in the group with hemorrhagic complications (69.4 s vs. 59.8 s; p = 0.01). In patients experiencing DIC, heparin dose and anti-factor Xa levels were lower, while no difference in activated clotting time and clotting time in INTEM and INTEM-HEPTEM were shown.Conclusions: Anti-factor Xa levels correlate better to heparin dose than activated clotting time. The use of anti-factor Xa assay instead of activated clotting time for dosing of unfractionated heparin could reduce thrombotic complications in neonates with congenital diaphragmatic hernia on ECMO support. The thromboelastometry showed no additional benefit for this purpose.

Download Full-text

Anti-Factor Xa Assay Is a Superior Correlate of Heparin Dose Than Activated Partial Thromboplastin Time or Activated Clotting Time in Pediatric Extracorporeal Membrane Oxygenation*

Pediatric Critical Care Medicine ◽

10.1097/pcc.0000000000000028 ◽

2014 ◽

Vol 15 (2) ◽

pp. e72-e79 ◽

Cited By ~ 65

Author(s):

Anna Liveris ◽

Ricardo A. Bello ◽

Patricia Friedmann ◽

Melissa A. Duffy ◽

Deepa Manwani ◽

...

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Partial Thromboplastin Time ◽

Factor Xa ◽

Activated Partial Thromboplastin Time ◽

Clotting Time ◽

Heparin Dose ◽

Membrane Oxygenation ◽

Activated Clotting Time

Download Full-text

Correlation Between Anti-Factor Xa, Activated Partial Thromboplastin Time, Activated Clotting Time, and R Time in Patients Supported With Continuous-Flow Left Ventricular Assist Devices

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2016.06.365 ◽

2016 ◽

Vol 22 (8) ◽

pp. S116

Author(s):

Ziad Taimeh ◽

Samit Roy ◽

Megan Fitzpatrick ◽

Marc Pritzker ◽

Peter Eckman ◽

...

Keyword(s):

Continuous Flow ◽

Factor Xa ◽

Left Ventricular ◽

Activated Partial Thromboplastin Time ◽

Ventricular Assist Devices ◽

Left Ventricular Assist Devices ◽

Clotting Time ◽

Ventricular Assist ◽

Activated Clotting Time ◽

Left Ventricular Assist

Download Full-text

Preoperative and intraoperative argatroban as anticoagulant for bridging a patient with heparin-induced thrombocytopaenia to lung transplantation

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezz294 ◽

2019 ◽

Vol 57 (5) ◽

pp. 1005-1006 ◽

Cited By ~ 1

Author(s):

Dong Kyu Oh ◽

Dong Kwan Kim ◽

Sehoon Choi ◽

Sang-Bum Hong

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Lung Transplantation ◽

Partial Thromboplastin Time ◽

Activated Partial Thromboplastin Time ◽

Clotting Time ◽

Membrane Oxygenation ◽

Activated Clotting Time ◽

Thrombotic Complications

Abstract A 65-year-old male was bridged to lung transplantation with veno-venous extracorporeal membrane oxygenation (ECMO). After experiencing heparin-induced thrombocytopaenia, heparin was replaced with argatroban. After 24 days, bilateral sequential lung transplantation was performed with argatroban anticoagulation. Intraoperative argatroban doses ranged between 0.4 and 0.6 μg/kg/min, resulting in activated clotting time of 169–216 s and activated partial thromboplastin time of 45–75 s. The patient was weaned from ECMO immediately after lung transplantation, and no bleeding or thrombotic complications were observed. He was discharged home on postoperative day 140.

Download Full-text

Factor Xa Inhibitory Profile of Apixaban, Betrixaban, Edoxaban, and Rivaroxaban Does Not Fully Reflect Their Biologic Spectrum

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029619847524 ◽

2019 ◽

Vol 25 ◽

pp. 107602961984752 ◽

Cited By ~ 5

Author(s):

Fakiha Siddiqui ◽

Debra Hoppensteadt ◽

Walter Jeske ◽

Omer Iqbal ◽

Alfonso Tafur ◽

...

Keyword(s):

Partial Thromboplastin Time ◽

Thrombin Generation ◽

Inhibitory Concentration ◽

Factor Xa ◽

Activated Partial Thromboplastin Time ◽

Inhibition Assay ◽

Clotting Time ◽

Activated Clotting Time ◽

Antithrombotic Effects

The currently available oral anti-Xa agents are claimed to produce their anticoagulant and antithrombotic effects solely by the inhibition of factor Xa. This study profiled various anti-Xa drugs in routinely used laboratory assays to demonstrate that their effects are not solely related to the anti-Xa activities. Apixaban, betrixaban, edoxaban, and rivaroxaban were obtained commercially. Native and citrated whole blood was used for the activated clotting time (ACT) and thromboelastography (TEG). Citrated plasma was used for monitoring the prothrombin time (PT), activated partial thromboplastin time (aPTT), Heptest, and prothrombinase-induced clotting time (PiCT) tests. An amidolytic method was used for the determination of anti-Xa effects. Thrombin-induced fibrinokinetics was monitored optically. Thrombin generation studies were carried out using the calibrated automated thrombogram. All of the anti-Xa agents produced concentration- and assay-dependent effects. In the ACT at 2.5 μg/mL and TEG at 1.0 μg/mL, edoxaban exhibited the strongest anticoagulation effect. In the PiCT, PT, and aPTT assay at 1 μg/mL, edoxaban showed stronger effects than other agents. The half maximal inhibitory concentration of these agents for the inhibition of factor Xa ranged from 340 to >1000 ng/mL. In the thrombin generation inhibition assay, apixaban showed the strongest activity. In the fibrinokinetics, different anti-Xa agents produced varying degrees of inhibition. These results demonstrate that the measured anti-Xa activity alone does not fully reflect the overall biologic spectrum of these agents.

Download Full-text

Use of Thromboelastogram in Venovenous Extracorporeal Membrane Oxygenation for a Patient with Pulmonary Hemorrhage due to Microscopic Polyangiitis

Case Reports in Critical Care ◽

10.1155/2019/7241264 ◽

2019 ◽

Vol 2019 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Chak-Kwan Tong ◽

Jun Jin ◽

Qian Du

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Microscopic Polyangiitis ◽

Pulmonary Hemorrhage ◽

Activated Partial Thromboplastin Time ◽

Clotting Time ◽

Heparin Dose ◽

Heparin Infusion ◽

Membrane Oxygenation ◽

Activated Clotting Time ◽

Venovenous Extracorporeal Membrane Oxygenation

Systemic heparinisation is required for extracorporeal membrane oxygenation therapy, to prevent clotting of circuit and formation of thrombus in patient. Activated clotting time (ACT) or activated partial thromboplastin time (aPTT) has been the mainstay of monitoring of heparin dose. Thromboelastogram (TEG) is increasingly being used again in recent years with the advancement in technology. Its clinical usefulness in the monitoring of anticoagulation of ECMO therapy is demonstrated in the case presented. Our patient suffered from severe hemoptysis due to active microscopic polyangiitis and respiratory failure. Heparin infusion was given at the initiation of ECMO support without further aggravation of hemoptysis. Dose of heparin was adjusted successfully with the integration of the clotting profile and TEG results.

Download Full-text

Clinical safety and cost of heparin titration using bedside activated clotting time

American Journal of Critical Care ◽

10.4037/ajcc1993.2.1.81 ◽

1993 ◽

Vol 2 (1) ◽

pp. 81-87 ◽

Cited By ~ 3

Author(s):

T Thomason ◽

B Riegel ◽

D Jessen ◽

Smith SCJr ◽

I Gocka ◽

...

Keyword(s):

Partial Thromboplastin Time ◽

Percutaneous Transluminal Coronary Angioplasty ◽

Heparin Therapy ◽

Activated Partial Thromboplastin Time ◽

Clotting Time ◽

Clinical Safety ◽

Activated Clotting Time ◽

Intravenous Heparin ◽

Transluminal Coronary Angioplasty ◽

Percutaneous Transluminal

OBJECTIVE: To evaluate the clinical safety of heparin titration and the procedural cost of anticoagulation measurement using bedside low-range activated clotting time. DESIGN: Quasi-experimental study using data gathered through retrospective record review. SETTING: Coronary care, medical intensive care and telemetry units of a community hospital. SUBJECTS: Sample of 102 patients undergoing elective percutaneous transluminal coronary angioplasty. INTERVENTION: Intravenous heparin therapy was titrated using low-range activated clotting time in 51 percutaneous transluminal coronary angioplasty patients. Data from this group were compared to a matched sample of 51 angioplasty patients whose intravenous heparin therapy was titrated using activated partial thromboplastin time. RESULTS: No differences in procedural, early or late complications were found between the groups. The cost of managing heparin therapy with low-range activated clotting time was less than with activated partial thromboplastin time. CONCLUSION: These results suggest that titrating heparin therapy based on bedside low-range activated clotting time for the angioplasty patients in this sample was as safe as with activated partial thromboplastin time. Use of bedside low-range activated clotting time saved money for the hospital.

Download Full-text

Factors associated with errors in the heparin dose response test: recommendations to improve individualized heparin management in cardiopulmonary bypass

Perfusion ◽

10.1177/0267659120952977 ◽

2020 ◽

pp. 026765912095297

Author(s):

Min-Ho Lee ◽

William Riley

Keyword(s):

Cardiopulmonary Bypass ◽

Dose Response ◽

Clotting Time ◽

Critical Aspect ◽

Heparin Dose ◽

Factors Associated ◽

Heparin Concentration ◽

Activated Clotting Time

Background: A critical aspect of cardiopulmonary bypass (CPB) is to achieve full anticoagulation to prevent thrombosis and consumptive coagulation without using excessive amount of heparin. This can be achieved with heparin dose response (HDR) test in vitro to calculate an individualized heparin bolus to reach a target activated clotting time (ACT) and heparin concentration. However, we often observe that the measured ACT (mACT) with the calculated heparin bolus gives significant errors, both positive (mACT is higher than expected) and negative (mACT is lower), from expected ACT (eACT). Methods: We performed a retrospective study of 250 patients who underwent cardiac surgery to attain an error distribution of the mACT from eACT with calculated heparin bolus. In addition, it is aimed to identify possible patterns of baseline ACT (bACT), calculated heparin concentration (CHC) and HDR slope that are associated with the significant positive and negative errors. Results: We found that individualized heparin bolus by HDR test is consistently underestimated while it gave a significant number of positive and negative errors. Further analysis indicates that significant negative errors correlate with high bACT and slope and low CHC while significant positive errors with low bACT and slope and high CHC. Conclusion: The mACT can be substantially different from eACT. The accuracy of the HDR test appears to be dependent upon bACT, slope, and CHC. Based on our analysis, we provide several recommendations and a flow chart to improve the quality of individualized heparin management on CPB.

Download Full-text

Impact of Apixaban On a Large Panel of Routine or More Specific Coagulation Assays.

Blood ◽

10.1182/blood.v120.21.2275.2275 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2275-2275

Author(s):

Jonathan Douxfils ◽

François Mullier ◽

Christian Chatelain ◽

Bernard Chatelain ◽

Dogné Jean-Michel

Keyword(s):

Atrial Fibrillation ◽

Drug Concentration ◽

Partial Thromboplastin Time ◽

Factor Xa ◽

Activated Partial Thromboplastin Time ◽

Plasma Drug Concentration ◽

Thrombin Time ◽

Plasma Drug ◽

Clotting Time

Abstract Abstract 2275 Introduction: Apixaban is direct factor-Xa inhibitor that reached the market for the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery. It is also being evaluated in the reduction of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome and in the prevention of stroke in patients with non-valvular atrial fibrillation. Thanks to its predictable pharmacokinetic profile, biological monitoring is not required. Nevertheless, evaluation of plasma drug concentration may be valuable in specific situations such as recurrent thrombosis, bleedings, before urgent surgery, in case of bridging and in case of at least two risk factors among the following ones: drug interactions with caution, moderate renal impairment and moderate hepatic impairment; Monitoring may also be useful in infants, pregnant women or in extreme body weights, although no relevant data on drug levels associated with approximate therapeutic and harmful ranges are currently available. Material and Methods: Apixaban was spiked at increasing concentrations (0, 5, 10, 20, 50, 100, 200 and 500 ng/mL) in pooled citrated normal human platelet poor plasma (PPP) to measure Prothrombin Time (PT) and dilute PT with different thromboplastin, Thrombin Generation Assay (TGA) with different inducers and activity on different anti-Xa chromogenic assays. Activated Partial Thromboplastin Time with different reagents, Thrombin Time (TT), Ecarin Clotting Time (ECT) and Reptilase Time (RT), measurement of fibrinogen (Clauss method and PT-derived method) and antithrombin (anti-IIa and anti-Xa based chromogenic assays) were also tested. We also evaluated the impact of apixaban on assays used for the determination of lupus anticoagulant such as the DRVV-T.. (Screen and Confirm) as well as the PTT-LA.. and the Staclot-LA.. . Results and Discussion: As mentioned in previous studies, PT showed a weak sensitivity towards apixaban in comparison with the plasma range obtained in short pharmacokinetic studies. Indeed, the concentration needed to double the clotting time was 154 ng/mL with the most sensitive reagent while the mean Cmax obtained in a short PK study after one oral intake of 5 mg apixaban (dose given in atrial fibrillation) was 96 ng/mL. Therefore, the sensitivity of PT is not strong enough to allow accurate quantitative measurement of the plasma drug concentration (Table 1). Activated Partial Thromboplastin Time presented a better sensitivity but showed a plateau after 100 ng/mL reflecting the uselessness of this test for the quantification of apixaban. Thrombin Time, ECT and RT were logically not affected while DRVV-T.. showed a sensitivity of 205 ng/mL (Screen), which is once again not enough sensitive. On the opposite, chromogenic anti-Xa assays seemed to be very sensitive (Figure 2 and Table 1). Nevertheless, the relation was not always linear and some methodologies needed to be adapted to ensure a broader range of application. TGA (Figure 1) may be useful to assess the pharmacodynamics effects of apixaban on the coagulation process. Nevertheless, the turn around time and the lack of standardisation are currently limitations that restrict the use of this method. In the case of the exploration of an haemorrhagic event, specific tests such as RT, fibrinogen (Clauss and PT-derived method (dFib)), TT and clotting factor activity may be used. Apixaban did not interfere with these tests. Antithrombin determination if also of importance and chromogenic anti-IIa based assays should be used in face of patients treated with apixaban to avoid misdiagnosis since an overvaluation of 12% by 100 ng/mL was shown using one chromogenic anti-Xa based assay. Conclusion: PT may not be used as screening test to assess the risk of bleedings. A more specific and sensitive assay such as chromogenic anti-Xa assays using calibrators should be used to correctly assess the concentration of apixaban. Determination of lupus anticoagulant using DRVV-T.. and PTT-LA.. or Staclot LA.. as well as the determination of antithrombin using factor-Xa based chromogenic assays, were influenced by apixaban. Finally, standardization of the time between the last intake of apixaban and the sampling is mandatory. Figures: Disclosures: No relevant conflicts of interest to declare.

Download Full-text